Ara-AC is a hydrid nucleoside combining the structural elements of arabinosyl cytosine and 5-azacytidine. During the past year, systematic studies were carried out to determine the mechanisms by which tumor cells acquire resistance to this agent. Three models were adopted: 1) spontaneous resistance, exemplified by the transplantable colon carcinoma 38; 2) acquired resistance provoked by cultivation of P388 cells in the presence of incremental concentrations of Ara-AC over 100 generations; 3) resistance provoked by mutagenesis with MNNG. In all three cases, the resistance was accompanied by a fall, and in some cases a deletion of deoxycytidine kinase, the enzyme responsible for inaugurating the anabolism of the drug. In the case of the colon carcinoma 38, a second enzymatic factor was identified, namely an abundant endowment with a cytosolic nucleoside triphosphatase, which prevents the accumulation of adequate levels of the proximate antimetabolite, Ara-AC-triphosphate. These studies were next extended to a panel of cultured human tumor cells. In these lines there was a positive correlation (r = 0.63) between deoxycytidine kinase levels and the IC50 of Ara-AC. It is therefore proposed that measurement of this kinase might well be of prognostic value in patients scheduled to receive Ara-AC in its forthcoming Phase I trials.